Agranulocytosis is an infrequent but potentially fatal complication associated with certain drugs that otherwise have less serious side effects and ordinarily are harmless to most patients. The complication is characterized by leukopenia (white blood count less than 2000/cu.mm.), a total absence of polymorphonuclear leukocytes (defined as less than 500/cu.mm.) and relative lymphopenia. If the disorder goes unrecognized and treatment with the drug is not discontinued, agranulocytosis will run a progressive course of increasing severity culminating in death from infection. If treatment with the drug is discontinued, complete recovery usually occurs. The period of greatest risk of agranulocytosis developing is in the first 3 to 12 weeks of treatment.
Antipsychotic drugs such as neuroleptics, tricyclic antidepressants and the benzodiazepines have been implicated in producing agranulocytosis. The most significant of these is the atypical neuroleptic drug, clozapine, whose chemical name is 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e]-[1,4]diazepine. Clinical studies have shown that clozapine is effective as an antipsychotic agent in patients who are refractory and/or intolerant to classical antipsychotic drug treatment. The compound was found to be superior to standard neuroleptics; and approximately 30% of the patients conservatively defined as being refractory to these neuroleptics significantly improved with clozapine treatment. At the same time, it was found that clozapine does not cause parkinsonism or tardive dyskinesia to the same extent as classical neuroleptics and that it does not elevate prolactin secretion. With regard to tardive dyskinesia, long term treatment with clozapine appears to have a therapeutic effect against this neuroleptic side-effect, particularly the more severe form, tardive dystonia.
Despite its advantages, development of clozapine has been hampered by the apparent increased risk of agranuylocytosis. Based on clinical data, the incidence in patients treated for 52 weeks with clozapine is approximately 2%. Because of this risk, patients on a clozapine regimen have to be monitored continually for hematological signs of agranulocytosis onset. A simple screening procedure which reduced or eliminated the hematological monitoring required in clozapine therapy would be highly desirable in view of the considerable therapeutic potential of clozapine for patients who are unresponsive to or intolerant of the standard neuroleptic drugs.